Assessment of peripheral blood CD4+ adenosine triphosphate activity in patients with rheumatoid arthritis

Objective

The ability of the ImmuKnow (Cylex) assay to predict the risk of infection in rheumatoid arthritis (RA) patients receiving synthetic or biological disease-modifying antirheumatic drugs (DMARDs) was examined.

Methods

The amount of adenosine triphosphate (ATP) produced by CD4+ cells in response to phytohemagglutinin was measured in whole blood from 117 RA patients without infection versus 17 RA patients with infection, and compared with results in 75 healthy controls.

Results

The mean ATP level was significantly lower in patients with infection compared to both healthy controls (P < 0.0005) and patients without infection (P = 0.040). Also, the mean ATP level in patients without infection was significantly lower than that in healthy controls (P = 0.012). There was no correlation between the ATP level and the Disease Activity Score in 28 joints.

Conclusion

ImmuKnow assay results may be effective in identifying RA patients at increased risk of infection, but the results showed no correlation with RA activity. Larger studies are required to establish the clinical advantages of this assay in RA treatment.     

Mechanisms of bone loss in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which destruction of bone in the joints causes major morbidity. Recent research has shed light on the cell and molecular mechanisms that lead to this osteolysis, all due directly or indirectly to the chronic inflammation. The aspects of this research covered in this review include the alteration of cell proliferation and survival that results in growth of the RA synovium. This process depends upon an increase in angiogenesis and local blood flow, which is also a feature of increased bone turnover. In addition, the inflammatory environment increases expression of chemokines, which are involved in the recruitment of monocytic osteoclast precursors. Chronic inflammation also promotes an overall catabolic state, with increased osteoclast differentiation and resorptive activity, driven by disregulation of receptor activator of NF-κB ligand (RANKL) and the synergistic activity of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1. Osteoclast survival is increased in this environment, but osteoblast differentiation and survival are decreased, with a consequent reduction in bone formation and a net loss of bone. Recognition of these processes and the factors involved will enable more effective and targeted treatments for RA.     

Mechanisms of bone loss in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease in which destruction of bone in the joints causes major morbidity. Recent research has shed light on the cell and molecular mechanisms that lead to this osteolysis, all due directly or indirectly to the chronic inflammation. The aspects of this research covered in this review include the alteration of cell proliferation and survival that results in growth of the RA synovium. This process depends upon an increase in angiogenesis and local blood flow, which is also a feature of increased bone turnover. In addition, the inflammatory environment increases expression of chemokines, which are involved in the recruitment of monocytic osteoclast precursors. Chronic inflammation also promotes an overall catabolic state, with increased osteoclast differentiation and resorptive activity, driven by disregulation of receptor activator of NF-κB ligand (RANKL) and the synergistic activity of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1. Osteoclast survival is increased in this environment, but osteoblast differentiation and survival are decreased, with a consequent reduction in bone formation and a net loss of bone. Recognition of these processes and the factors involved will enable more effective and targeted treatments for RA.     

The osteoclast: a potential therapeutic target of bone and joint destruction in rheumatoid arthritis

Abstract

There is accumulating evidence that osteoclasts, the primary cells responsible for bone resorption, are involved in bone and joint destruction in rheumatoid arthritis (RA). Recent progress in bone cell biology has revealed the molecular mechanism of osteoclast differentiation and bone resorption by mature osteoclasts. We here highlight the potential role of RANKL–RANK pathways in bone destruction in RA. We also describe our recent trials on gene therapy of arthritic joint disease targeting osteoclasts by regulating Src kinase activity in the cells.     

The osteoclast: a potential therapeutic target of bone and joint destruction in rheumatoid arthritis

There is accumulating evidence that osteoclasts, the primary cells responsible for bone resorption, are involved in bone and joint destruction in rheumatoid arthritis (RA). Recent progress in bone cell biology has revealed the molecular mechanism of osteoclast differentiation and bone resorption by mature osteoclasts. We here highlight the potential role of RANKL–RANK pathways in bone destruction in RA. We also describe our recent trials on gene therapy of arthritic joint disease targeting osteoclasts by regulating Src kinase activity in the cells.     

Total knee arthroplasty for rheumatoid arthritis

Total knee arthroplasty is a proven technique for the management of deformity and unremitting pain in the rheumatoid arthritic knee. Many important considerations must be taken into account in order to maximize the results of total knee replacement in this challenging patient population.     

Total knee arthroplasty for rheumatoid arthritis

Abstract

Total knee arthroplasty is a proven technique for the management of deformity and unremitting pain in the rheumatoid arthritic knee. Many important considerations must be taken into account in order to maximize the results of total knee replacement in this challenging patient population.     

Scientific basis for the efficacy of combined use of antirheumatic drugs against bone destruction in rheumatoid arthritis

Finding a means to ameliorate and prevent bone destruction is one of the urgent issues in the treatment of rheumatoid arthritis. Recent studies revealed bone-resorbing osteoclasts to be essential for arthritic bone destruction, but to date there has been scarce experimental evidence for the underlying mechanism of the bone-protective effect of antirheumatic drugs. Here we examined the effects of one or a combination of disease-modifying antirheumatic drugs (DMARDs) on osteoclast differentiation to provide a cellular and molecular basis for their efficacy against bone destruction. The effects on osteoclast precursor cells and osteoclastogenesis-supporting cells were distinguished by two in vitro osteoclast culture systems. Methotrexate (MTX), bucillamine (Buc) and salazosulphapyridine (SASP) inhibited osteoclastogenesis by acting on osteoclast precursor cells and interfering with receptor activator of NF-κB ligand (RANKL)-mediated induction of the nuclear factor of activated T cells (NFAT) c1. MTX and SASP also suppressed RANKL expression on osteoclastogenesis-supporting mesenchymal cells. Interestingly, the combination of three antirheumatic drugs exerted a marked inhibitory effect on osteoclastogenesis even at a low dose at which there was much less of an effect when administered individually. These results are consistent with the reported efficacy of combined DMARDs therapy in humans and suggest that osteoclast culture systems are useful tools to provide an experimental basis for the bone-protective effects of antirheumatic drugs.     

The role of leukotrienes in immunopathogenesis of rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of joints for which there is no strict cure. However, conventional medications can reduce inflammation, relieve pain, and slow joint damage. Leukotrienes are a family of paracrine agents derived from oxidative metabolism of arachidonic acid. Synthesis of lipid mediators and subsequent induction of receptor activity are tightly regulated under normal physiological conditions, so that enzyme and/or receptor dysfunction can lead to a variety of clinical signs and symptoms of disease, such as local pain and tissue edema. In these tissues, immunocompetent cells accumulate at the site of injury, contributing to tissue damage and perpetuation of the disease process. Leukotrienes (often leukotriene B4) as potent chemotactic agents can provoke most signs and symptoms in rheumatoid arthritis by initiating, coordinating, sustaining, and amplifying the inflammatory response, through recruitment of leukocytes. A number of studies have reported that pharmacological modulation in this field can significantly attenuate clinical manifestations associated with different inflammatory pathologies.     

Isotypes of rheumatoid factors in rheumatoid arthritis and chronic liver diseases

We studied isotype-specific rheumatoid factors (RFs) to clarify their significance in rheumatoid arthritis (RA) and to verify the difference in RF isotypes between RA and chronic liver diseases (CLD). Isotype-specific RFs in RA and in CLD were measured by enzyme-linked immunosorbent assay (ELISA). Most sera (n = 51, 94.1%) from RA patients contained some kind of RF isotypes (92.1% for IgM RF, 76.4% for IgG RF, and 43.1% for IgA RF), and seronegative RA by ELISA was seen in only 11.8% (n = 6). The most characteristic combination of RF isotypes in active RA was IgG, IgA, and IgM. This combination of RF isotypes changed to IgG plus IgM, according to the diminution of RA activity; then, we found only IgM RF in inactive RA. The titers of each RF isotype also decreased in parallel with the activity of RA. IgA RF seemed to be the most sensitive factor for evaluating the activity of RA. In CLD, almost the same high frequency (n = 49, 89.8% for IgM RF, 59.2% for IgG RF), with the same titer levels seen in RA, was observed. On the other hand, IgA RF was significantly lower in frequency (n = 9, 18.4%) and in titer, compared with the finding in RA. Surprisingly, even in CLD, true seronegativity by ELISA was also found in very few patients (n = 4, 8.1%). In CLD, positive RFs detected by agglutination assay were seen more often in chronic hepatitis than in liver cirrhosis. In RA patients, significant associations of IgA RF and the serum concentration of IgA, and IgG RF and the serum concentration of IgG, were observed. On the other hand, in CLD patients, significant associations of IgG RF and the serum IgG concentration, and of IgM RF and the serum IgM concentration, were observed. These results indicated that IgA RF in active RA is the most characteristic RF isotype distinguishing it from other nonrheumatic diseases, as well as from inactive RA. RF isotypes reflected the background polyclonal B-cell activation in different manners in both diseases. In CLD, RF isotypes seemed to be disease-related immunological disorders reflecting disease progression. Received: February 17, 2000 / Accepted: July 5, 2001     

Acute destruction of the hip joints and rapid resorption of femoral head in patients with rheumatoid arthritis

Abstract

We report three rheumatoid arthritis (RA) cases with acute destruction of hip joint and rapid resorption of femoral head. The condition occurred in less than 6 months and closely resembled rapid destructive coxarthrosis. All three patients were postmenopausal women with active RA who had been taking steroids. Two of the patients were taking prednisolone (PSL) of over 20?mg as maximum dose per day, and all patients were resistant to disease-modifying anti-rheumatic drugs (DMARDs). Other than the problems of their hip joints, one had a giant bursitis around the pathological side of the hip joint, another had multiple rheumatoid nodules and skin infarction, and the other suffered from insufficiency fracture of the contralateral femoral subcapital lesion. As a result, all of them had total hip arthroplasty. We recommend taking repetitive radiographs for RA patients with continuing severe hip pain.     

Acute destruction of the hip joints and rapid resorption of femoral head in patients with rheumatoid arthritis

We report three rheumatoid arthritis (RA) cases with acute destruction of hip joint and rapid resorption of femoral head. The condition occurred in less than 6 months and closely resembled rapid destructive coxarthrosis. All three patients were postmenopausal women with active RA who had been taking steroids. Two of the patients were taking prednisolone (PSL) of over 20 mg as maximum dose per day, and all patients were resistant to disease-modifying anti-rheumatic drugs (DMARDs). Other than the problems of their hip joints, one had a giant bursitis around the pathological side of the hip joint, another had multiple rheumatoid nodules and skin infarction, and the other suffered from insufficiency fracture of the contralateral femoral subcapital lesion. As a result, all of them had total hip arthroplasty. We recommend taking repetitive radiographs for RA patients with continuing severe hip pain.     

Atypical mycobacteriosis in two patients with rheumatoid arthritis

We report two cases of rheumatoid arthritis (RA) with atypical mycobacteriosis. Opportunistic infections are critical complications for rheumatic diseases. The use of steroids or immunosuppressants may increase the risk of opportunistic infections. However, these reports are rare in that they demonstrate atypical mycobacterial infections as complications of RA, even though no immunosuppressive agents were used. We discuss the characteristics of atypical mycobacterial infections of the lung in RA. Received: January 22, 2001 / Accepted: July 21, 2001     

Pharmacokinetics and efficacy of low-dose methotrexate in patients with rheumatoid arthritis

This article evaluates the relationship between the pharmacokinetics of methotrexate (MTX), its efficacy in the treatment of rheumatoid arthritis (RA), and serum folic acid (FA) levels. The pharmacokinetics of MTX was studied in 29 patients with RA treated with low-dose MTX. The weekly dose of MTX was given orally at 2–4mg every 12h over a period of 24–36h. Blood samples were taken 4h after the first administration in any given week. A Bayesian method was used to estimate individual MTX pharmacokinetic variables. We then investigated the efficacy of MTX and the serum FA levels in these patients. We examined C-reactive protein levels (CRP) and the erythrocyte sedimentation rate (ESR), and analyzed the values obtained before and after MTX treatment in order to evaluate the efficacy of the MTX treatment. The degree of improvement in CRP and ESR was significantly correlated with the length of time the MTX concentration–time curve remained above 0.02µM in one week. Furthermore, the degree of improvement in CRP was also significantly correlated with the area under the concentration–time curve (AUC) for MTX. These results suggest that serum MTX measurements could be useful in determining individual patient regimens.     

Ultrasonographic evaluation of synovial effusion and synovial proliferation pattern in the knee joints of patients with rheumatoid arthritis

In the present study, 49 knee joints of 26 patients with rheumatoid arthritis and 17 knee joints of 17 healthy subjects were ultrasonographically examined. Lateral, superior, and medial aspects of the patella were scanned using an ultrasonograph with a 7.5-MHz annular array transducer to evaluate the thickness of synovial effusion and the synovial proliferation pattern. The overall mean thickness of synovial effusion (mean of all three sites) in the knee joints was 4.9 ± 3.4 mm for rheumatoid arthritis patients and 1.4 ± 0.5 mm for healthy subjects. In rheumatoid arthritis patients, the mean thickness of synovial effusion at the superior aspect of the patella (6.5 ± 4.1 mm) was significantly greater than that at the lateral aspect (4.5 ± 4.8 mm) (P < 0.05) and the medial aspect (4.0 ± 3.1 mm) (P < 0.01). Patients with the villonodular pattern of synovial proliferation had a shorter duration of disease than those with uniform thickening or an overlapping pattern. Received: May 1, 2001 / Accepted: August 6, 2001     

Doppler sonographic evaluation of effect of treatment with infliximab (Remicade) for rheumatoid arthritis

Synovial vascularization in the knee joints of six patients with rheumatoid arthritis who were treated with infliximab was evaluated by Doppler sonography. Power Doppler sonography demonstrated a significant reduction of color flow signals (P < 0.05), and spectral Doppler sonography demonstrated a significant increase in vascular resistance (P < 0.05) at week 6 (after three injections) evaluation of the therapy. A significant decrease in the number of tender joints (P < 0.05) and C-reactive protein value (P < 0.05) was also observed in these patients.     

生物制剂治疗类风湿关节炎的研究进展

类风湿关节炎(RA)是一类常见致残性自身免疫性疾病,传统的治疗药物主要有非甾体抗炎药、糖皮质激素等,但仍有部分病人病情无法控制,最终导致关节进行性破坏。近年来,多种生物制剂的出现为难治性RA的治疗带来了希望,可以有效控制风湿病活动和改善患者生活质量。该文就生物制剂在RA中的治疗进展作一综述。     

Gynecomastia associated with low-dose methotrexate therapy for rheumatoid arthritis

A 68-year-old man with a 3-year history of rheumatoid arthritis (RA) developed gynecomastia 3 months after beginning oral low-dose methotrexate (MTX) therapy. Four months after MTX therapy was discontinued, the gynecomastia symptoms improved. Only eight cases of gynecomastia resulting from low-dose MTX administration have been reported worldwide, and no cases have previously been reported in Japan. Although it occurs infrequently, gynecomastia resulting from low-dose MTX therapy should be considered in male patients with RA.     

Gynecomastia associated with low-dose methotrexate therapy for rheumatoid arthritis

Abstract

A 68-year-old man with a 3-year history of rheumatoid arthritis (RA) developed gynecomastia 3 months after beginning oral low-dose methotrexate (MTX) therapy. Four months after MTX therapy was discontinued, the gynecomastia symptoms improved. Only eight cases of gynecomastia resulting from low-dose MTX administration have been reported worldwide, and no cases have previously been reported in Japan. Although it occurs infrequently, gynecomastia resulting from low-dose MTX therapy should be considered in male patients with RA.     

Twenty-four-week follow-up examination of a leukocytapheresis therapy in rheumatoid arthritis

Several clinical trials have demonstrated that leukocytapheresis (LCAP) is a safe and effective therapy for patients with refractory rheumatoid arthritis (RA). However, most of those reports were limited to short-term clinical observation. We have treated 11 RA patients with LCAP and observed them for 24 weeks after the final administration. The 11 cases included 3 diabetes patients, 2 patients with interstitial pneumonia, 1 patient with diffuse panbronchiolitis, and 1 patient with old pulmonary tuberculosis. Alternative therapies for all of these patients were considered difficult. Once-a-week LCAP administration was added for 5 weeks to the previous therapeutic regime in all patients, and the treatment efficacy was prospectively qualified. At 4 weeks after the final LCAP therapy, 8 of the 11 patients (73%) had achieved an American College of Rheumatology (ACR) 20% response, and 3 of the 11 (27%) had achieved both ACR 50% and ACR 70% responses. Although the efficacy decreased after the observation periods, an ACR 20% response was maintained in 5 patients (45%) at 24 weeks. Although only a limited number of patients were examined in this study, the results suggested that LCAP therapy will be beneficial to RA patients, including patients who cannot be treated with tumor necrosis factor inhibitors or conventional disease-modifying antirheumatic drugs.